Bufuralol, a new beta-adrenoceptor blocking agent in a series of benzofuran-2-ethanolamines. Part 2: pharmacology.

1-(7-Ethylbenzofuran-2-yl)-2-tert.-butylamino-1-hydroxyethane hydrochloride (bufuralol) is a non-selective beta-adrenoceptor blocking agent which closely resembles propranolol in its properties, including potency. Bufuralol is devoid of alpha-adrenoceptor blocking activity but possesses beta-adrenoceptor agonist activity. beta-Adrenoceptor blocking activity resides mainly in the (-)-isomer though membrane stabilising properties are associated with both optical isomers.

Metabolic deacetylation: in vitro and in vivo studies in man, rat, dog and rhesus monkey with isomeric tetrahydroisoquinolyl derivatives of 3,4-dimethylbenzyl acetate.

The pharmacological activities of a racemic mixture of tetrahydroisoquinolyl derivatives of 3,4-dimethylbenzyl acetate, (+/-) Ro 03-4661 and the corresponding resolved isomers (+) Ro 03-4661 and (--) Ro 03-4661 have been studied in rat and rhesus monkey. The racemate and the (--) isomer showed narcotic analgesic activity by the oral route in both species. Drug metabolism studies indicated that the activity was probably due to metabolic Deacetylation to the corresponding carbinol Ro 03-4632. deacetylation did not occur in the dog, but was observed in the rat and rhesus monkey. In both these species the hydrolysis was more extensive after oral than parenteral administration. In vitro studies also showed considerable species variation in the ability of blood and tissue esterases to hydrolyse the different stereochemical isomers.

An investigation of the tachycardia produced by intracerebro-ventricular injections of isoprenaline in mice.

1. Isoprenaline, 3.5-20 ng, injected intracerebroventricularly in atropinized mice under pentobarbitone anaesthesia produced a dose-dependent tachycardia. 2. Pretreatment with either reserpine or pempidine blocked nervously-mediated tachycardia as shown by marked reduction of that due to stimulation of the spinal outflow in pithed mice. After pretreatment with these drugs, intracerebroventricular isoprenaline caused tachycardia of a similar degree and time course to that in mice not so pretreated. 3. Pretreatment with either reserpine or pempidine caused supersensitivity to the tachycardia due to intravenous isoprenaline. 4. When allowance was made for this supersensitivity in the effect of intracerebroventricular isoprenaline in pretreated mice, a small dose-dependent residual effect remained that could be attributed to leakage of isoprenaline into the peripheral circulation. 5. This was confirmed by the appearance of a late-developing tachycardia on intracerebroventricular injection of isoprenaline in spinal mice. 6. It is therefore concluded that the tachycardia caused by intracerebroventricular isoprenaline in mice is, at least initially, of central origin.

The detection of differential beta-adrenoceptor blockade in the cat.

1. Tachycardia and bronchodilatation were produced by intravenous dimethylphenylpiperazinium iodide (DMPP) in the spinal or pithed cat. Responses other than those involving beta-adrenoceptors were minimized by appropriate blocking agents.2. With intact adrenals, both the tachycardia and bronchodilatation with 10 mug/kg DMPP were equal to those with 1 mug/kg adrenaline.3. After adrenalectomy, tachycardia with 100 mug/kg DMPP was equal to that with 1.5 mug/kg adrenaline, but the bronchodilatation was equal to that with only 0.3 mug/kg. This difference may reflect the relative activity of the sympathetic supply to the organs.4. After adrenalectomy, propranolol was 3 times as effective against bronchodilatation due to DMPP as against tachycardia. Practolol was inactive against bronchodilatation.5. With intact adrenals, propranolol reduced both tachycardia and bronchodilatation due to DMPP equally. Propranolol also antagonized equally both effects of adrenaline in the pithed cat after adrenalectomy.6. In the spinal cat, propranolol caused bradycardia and bronchoconstriction that persisted after adrenalectomy or pithing. It was reduced by pempidine and guanethidine and is attributed to spontaneous adrenergic neuronal activity.7. The Appendix describes a device for cycle-by-cycle spirometry and correction for zero drift of a micromanometer, used in this study for the continuous recording of bronchial resistance.

Supersensitivity of salivation in response to pilocarpine after withdrawal of chronically administered hyoscine in the mouse.

1. The duration of the effect of a single large dose of hyoscine, in reducing the salivary response of mice to pilocarpine, was established as less than 66 hours.2. Supersensitivity was observed, after daily oral dosing with hyoscine, in the increased salivation of mice in response to pilocarpine injected at least 66 h after withdrawing hyoscine.3. The minimum duration of pretreatment with hyoscine that resulted in supersensitivity was 5 days. The daily dose was more effective if divided.4. The period after withdrawal for which supersensitivity could be detected was 6 days.5. The maximum salivary response to pilocarpine was increased by chronic hyoscine pretreatment.6. The antagonism of a single dose of hyoscine to pilocarpine salivation, as expressed by the dose-ratio of pilocarpine, was not altered by chronic hyoscine pre-treatment.

Assessment of the effectiveness of -adrenoceptor blocking agents towards cardiac and bronchiolar responses of the pithed guinea-pig to electrical stimulation of the spinal outflow.

1. The responses of heart rate and resistance to lung inflation of the pithed guinea-pig on electrical stimulation of the thoracic spinal roots could be related to similar responses to injected catecholamines, such that dose-stimulus frequency relations could be plotted.2. The range of frequency of stimulation that was equi-effective with a dose range of injected catecholamines was higher for effects on air overflow than for heart rate. The slope of the relations for heart rate also differed from that for air overflow. These features may reflect a difference in effectiveness of the sympathetic innervation of heart and bronchial tree.3. Propranolol was equally effective in reducing the responses of heart rate and air overflow to injected noradrenaline. Practolol was somewhat more active against the effects of noradrenaline on air overflow than on heart rate, though equally active against the effects of isoprenaline.4. For the assessment of equivalent blockade of the effects of cord stimulation on heart rate and air overflow, frequency-ratios corresponding to a noradrenaline dose-ratio of 2 were derived from the slopes of the dose-frequency relations; for air overflow this value was approximately 2 and for heart rate approximately 1.4.5. When the doses required to produce these degrees of blockade were computed from the dose-response relations for blockade of the effects of cord stimulation by propranolol, they were found to be similar for effects on heart rate and air overflow. For practolol, the effective dose for block of heart rate increase was found to be lower than that for air overflow.

Effect of beta-adrenoceptive blocking agents on the response to bronchoconstrictor drugs in the guinea-pig air overflow preparation. Appendix describing a new modification of the air overflow method.

1. Propranolol augmented the bronchoconstrictor response to methacholine or histamine, recorded by air overflow in the anaesthetized, vagotomized guinea-pig.2. After adrenalectomy, propranolol was still active, though less so than before.3. In the pithed guinea-pig, there was no augmentation of the effect of bronchoconstrictors on air overflow. The action of propranolol could thus be due to the beta-adrenoceptor blockade of compensatory sympathetic bronchodilator activity, as concluded by McCulloch, Proctor & Rand (1967).4. Electrical stimulation of the thoracic region of the spinal cord of the pithed guinea-pig reduced the effect of bronchoconstrictors on air overflow. This reduction could be blocked by propranolol; practolol was much less effective.